Mucosal pathogens of the gastrointestinal tract must penetrate layers of mucus in order to establish infection of the underlying mucosal epithelium. The fundamental biological question our research addresses is whether mucosal colonization is by random chance or a function of genetic traits that direct the process. We are using the human gastric pathogen Helicobacter pylori as a model system to study mucosal colonization. We hypothesize that H. pylori responds rapidly to changes in local acidity in gastric mucus, through motility-linked chemoreceptors, that monitor temporal changes in gastric acidity;and (ii) that acid pH taxis is essential for primary colonization and for persistence by enabling bacteria to escape extreme acid stress. To test this hypothesis we have developed several pH taxis assays in which H. pylori displays negative chemotactic responses to acids (not to bases) and in these assays non-gastric species H. hepaticus and Campylobacter jejuni are not pH tactic. We determined that novel chemoreceptor TIpB is required for both pH taxis and for gastric colonization. We propose the following specific aims to further test the pH taxis hypothesis: (Aim I) To isolate TIpB function by deletion of the three other chemoreceptor genes to validate TIpB function, determine acid thresholds and the relative abundance of TIpB and other Tips and by screening gastric and non-gastric species of Helicobacter to determine whether TIpB and acid sensing are unique to gastric species;(Aim II) TIpB contains unique periplasmic and HAMP domains that might participate in acid sensing and both deletion and site directed mutagenesis scanning will be used to identify which domains sense acid (periplasmic or cytoplasmic) and whether protonation of key histidine or other amino acids is required for signal transduction;(Aim III) We propose to determine how the urease system (pH stasis) and global response regulators ArsRS and HP1043 (acid stress) interface with rapid acid pH tactic behavior in directing acid survival, gastric colonization and life long persistence. Relevance: It is remarkable that H. pylori can survive and display acid pH taxis in 100 mM hydrochloric acid, a feat unmatched by any microbial pathogen studied to date. Understanding the fundamental mechanisms associated with acid survival and gastric colonization underpins all eradicative strategies from vaccines to novel therapeutics against a pathogen that infects half of the world's population.